Based on our understanding of envelope-based mechanisms of humoral evasion, we have attempted to design envelope-based immunogens with these mechanisms disabled. Such modied immunogens with weakened defenses may elicit more broadly neutralizing antibodies. We have also devised protein scaffolding technologies, as a means of presenting structural mimics of the epitopes of broadly neutralizing antibodies to assist in their re-elicitation. Scaffolds can be non-homologous proteins, identified through structural searches of the entire Protein Data Bank (PDB). Alternatively, scaffolds can be homologous proteins, which are structurally similar, but antigenically distinct from the HIV-1 envelope glycoproteins. An alternative to scaffolding involves resurfacing, where the surface of a molecule, not involved in eliciting a desired response, is altered between prime and boost phases of immunization. Third, we have been coupling epitope mimics to highly immunogenic carrier proteins or expressing in the context of self-assembling nanoparticles, which have substantially higher immunogenicity than the monovalent or trivalent immunogens. In additional to such designer immunogens, we have also been investigating how insights from B cell ontogeny of broadly neutralizing antibodies identifies difficult steps in the elicitation process, which might be influenced by immunization; related antibody-lineage based design is also being explored.